Effects of block copolymer properties on nanocarrier protection from in vivo clearance.

Abstract

Drug nanocarrier clearance by the immune system must be minimized to achieve targeted
delivery to pathological tissues. There is considerable interest in finding in vitro
tests that can predict in vivo clearance outcomes. In this work, we produce nanocarriers
with dense PEG layers resulting from block copolymer-directed assembly during rapid
precipitation. Nanocarriers are formed using block copolymers with hydrophobic blocks
of polystyrene (PS), poly-ε-caprolactone (PCL), poly-D,L-lactide (PLA), or poly-lactide-co-glycolide
(PLGA), and hydrophilic blocks of polyethylene glycol (PEG) with molecular weights
from 1 kg/mol to 9 kg/mol. Nanocarriers with paclitaxel prodrugs are evaluated in
vivo in Foxn1(nu) mice to determine relative rates of clearance. The amount of nanocarrier
in circulation after 4h varies from 10% to 85% of initial dose, depending on the block
copolymer. In vitro complement activation assays are conducted to correlate in vivo
circulation to the protection of the nanocarrier surface from complement binding and
activation. Guidelines for optimizing block copolymer structure to maximize circulation
of nanocarriers formed by rapid precipitation and directed assembly are proposed,
relating to the relative sizes of the hydrophilic and hydrophobic blocks, the hydrophobicity
of the anchoring block, the absolute size of the PEG block, and polymer crystallinity.
The in vitro results distinguish between the poorly circulating PEG(5k)-PCL(9 k) and
the better circulating nanocarriers, but could not rank the better circulating nanocarriers
in order of circulation time. Analysis of PEG surface packing on monodisperse 200
nm latex spheres indicates that the size of the hydrophobic PCL, PS, and PLA blocks
are correlated with the PEG blob size. Suggestions for next steps for in vitro measurements
are made.